Therapeutic Delivery of Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miR-143-3p Inhibits Myocardial and Systemic Inflammation and Attenuates Sepsis-Related Myocardial Injury.

Sepsis-related myocardial injury (SRMI) is a major contributor to mortality in septic patients, driven by uncontrolled inflammation and macrophage dysregulation. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) possess immunomodulatory properties, but their cardioprotective mechanisms remain unclear. Here, we investigated whether BMSC-Exos deliver microRNA-143-3p (miR-143-3p) to reprogram macrophages and attenuate SRMI. Exosomes were isolated from murine bone marrow mesenchymal stem cells and characterized by electron microscopy, nanoparticle tracking analysis, and immunoblotting. In lipopolysaccharide-stimulated macrophages, BMSC-Exos promoted a shift from pro-inflammatory M1 to reparative M2 polarization, and reduced pro-inflammatory cytokine secretion. In a mouse model of endotoxemia, BMSC-Exo administration improved seven-day survival, preserved cardiac function, decreased circulating myocardial injury markers, and increased the proportion of cardiac M2 macrophages. MicroRNA sequencing identified miR-143-3p as highly enriched in BMSC-Exos but downregulated in circulating exosomes from septic mice. Delivery of miR-143-3p mimics recapitulated the protective effects of BMSC-Exos, while inhibition of miR-143-3p exacerbated injury. Mechanistically, miR-143-3p directly targeted Toll-like receptor 4 (TLR4) and suppressed the downstream myeloid differentiation primary response 88/nuclear factor-κB (MyD88/NF-κB) signaling pathway. Furthermore, TLR4 knockdown phenocopied the anti-inflammatory and M2-polarizing effects of miR-143-3p. These findings indicate that BMSC-Exos attenuate SRMI by transferring miR-143-3p to macrophages, where it inhibits TLR4/MyD88/NF-κB signaling and promotes M2 polarization, highlighting a potential therapeutic strategy for septic cardiac injury.